Lecture 10; Variability due to genetics Flashcards
Where can inherited differences in the disposition of drugs occur?
Absorption Distribution Metabolism Excretion Drug receptor targets
What are drug metaboliser traits?
- Poor metabolisers
- Intermediate metabolisers
- Extensive metabolisers (Normal reference value)
- Ultra rapid metabolisers
Write some notes on poor metaboliser trait:
- Inherited loss of function of a drug metabolising enzyme can result in no enzyme activity
- The poor metaboliser trait may lead to higher drug levels in the blood and this might result in increased risk of an adverse drug reaction compared with individuals with ‘normal’ metabolism
- Typically autosomal recessive (co-dominant)
What is the function of omeprazole and what clears it?
Omeprazole
- Proton pump inhibitor (irreversible)
- H/K ATPase in the gastric parietal cells
CYP2C19 is major route of clearance
What happens to people with two copies of null function CYP2C19 on omeprazole?
- They will be poor metabolisers of omeprazole
- Omeprazole concentrations will be elevated due to decreased renal clearance
- This can be detected by measuring metabolic ratio
What is the metabolic ratio?
Drug/metabolite plasma concentration = metabolic ratio
High ratio = poor metaboliser
Low ratio = Extensive metaboliser
What can happen with CYP2C19 genetic variants?
- Compound heterozygote but still homozygous for null function
I.e theres multiple gene variants that can lead to null function
Is high omeprazole due to null function CYP2C19 likely to be toxic?
- Omeprazole has a wide therapeutic index
- Unlikely to be substantially toxic
- But a wide range of concentrations can be given to effectively suppress GA secretion
What is clopidogrel?
Clopidogrel is used as antiplatlet therapy (combined with aspirin) after percutaneous coronary intervention (i.e stent) to minimise the risk of further ischeamia due to thrombosis
Prodrug that is bioactivated by CYP2C19
What are the range of genetic variations that might influence clopidogrel?
- 17 carriers = Ultra rapid metabolisers
* 2 carriers = Intermediate or poor metabolisers
Whats the risk for *17 and *2 carriers on clopidogrel:
- 17 = Increased risk of excessive bleeding, but, less chance of another CVE
- 2 = Increased risk of stent thrombosis (attenuated pharmacodynamic response) BUT no increased risk of another CVE
What else can you do for people on clopidogrel who carry variant genes?
P2Y12 inhibitors: Prasugrel and ticagrelor, do not require metabolic conversion
- But higher bleeding risk than clopidogrel
- More effective at prevent ischeamic events
Describe the major CYP2D6 gene variants:
Gene duplication (3 or 4 copies) = Ultra rapid metabolisers
SNP = *4 or *6 , no function alleles, Poor metabolisers
Describe codeine metabolism:
- Analgesic properties of codeine require its conversion to morphine by CYP2D6
- Morphine and its metabolite; Morphine-6-glucuronide are active at its receptor.
- 50-70% codiene is metabolised to codiene-6-glucuronide and is eliminated
Tramadol is also a CYP2D6 substrate, what will prescribing the standard dose to a poor metaboliser lead to?
Sub-therapeutic concentrations
What is irinotecan (SN38)?
Anti-neoplastic effects of SN-38 is due to the potential inhibition of DNA topoisomerase
= Treatment of colorectal cancer
Narrow therapeutic index
Eliminated by hepatic glucornidation (catalysed by UGT1A1 enzyme)
What are some variants in UTG1A1?
2BP insertion into UTG1A1 gene = UGT1A1*28
Decreases transcription and translation so produces 25% less enzyme and 50% Lower enzyme activity
The influence on clearance is predictable in manner
What is the potential toxicity of UGT1A1*28?
Risk of severe toxicity - Grade 3-4 neutropenia
Whats the further implications of UGT1A1 activity and irinotecan?
- Maximum dose was based on patients with unknown UGT1A1
- Thus people who are not poor metabolisers may be underdosed.
What is azathioprine?
- Immunosuppressive medication
- Guanine analog that acts as an antimetabolite (interferes with de novo guanine synthesis for DNA and RNA)
- Leucocytes rely on de novo synthesis of purines (rather than salvage)
- It is a prodrug (Azathioprine -> 6-mercaptopurine)
Describe the inherited deficiency in TMPT:
- Thiopurine methyl transferase (TMPT) is the major route of elimination of 6-MP
- Multiple non-functional alleles
- Increased risk of life
- Individuals who are poor metabolisers should receive a 10 fold lower starting dosage
When is it important to consider the role of pharmacogenetic variability:
- Is metabolic clearance an important/major route of elimination of the drug from the body?
- Does the drug have one (or a limited number) of metabolic routes of elimination?
- Is the drug biotransformed into an active or inactive metabolite?
- Is there a narrow therapeutic index for the drug?
Grab the blue table from the end of the slides and make sure you can complete it
Yes
